Soluble compositions of triphenylethylene antiestrogens

ABSTRACT

Aqueous compositions of nonsteroidal triphenylethylene antiestrogens for pharmaceutical use comprising as a solubility enhancing agent a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen, optionally together with an organic water miscible co-solvent such as polyethylene glycol (PEG), propylene glycol, ethanol or isopropanol.

This is a division of application Ser. No. 09/868,179, filed on October2, 2001, now U.S. Pat. No. 6,632,841, which is a national stage filingof PCT International Application No. PCT/FI99/01046, filed on December16, 1999, which claims the benefit of priority to Finnish patentapplication no. 982733, filed on Dec. 17, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to aqueous solutions of nonsteroidaltriphenylethylene antiestrogens for pharmaceutical use and to methodsfor the preparation thereof.

Toremifene, tamoxifen, 3-hydroxytamoxifen (droloxifene),4-hydroxy-tamoxifen, idoxifene, raloxifene, levormeloxifene,centchroman, clomiphene and their pharmaceutically acceptable salts areexamples of nonsteroidal triphenylethylene antiestrogens useful in thetreatment of estrogen dependent disorders, e.g. in the prevention ortreatment of estrogen receptor positive breast cancer. This class ofcompounds share the triphenylethylene structure and the compounds aregenerally very poorly soluble to water. There is a need for stableaqueous formulations of nonsteroidal triphenylethylene antiestrogens andtheir pharmaceutically acceptable salts, which would be suitable fore.g. high concentration parenteral, transdermal or topical formulations.Parenteral formulations of toremifene in the form of an emulsion,liposome or cyclodextrin complex have been described in WO 93/11757.Transdermal formulations of toremifene inDMSO/ethanol/methylcellulose/water have been described in WO 93/19746.Percutaneous hydroalcoholic gel of 4-hydroxytamoxifen has been describedin U.S. Pat. No. 4,919,937. However, these prior formulations arecumbersome to prepare, are irritating or do not provide sufficientlyhigh concentration solutions of nonsteroidal triphenylethyleneantiestrogens.

SUMMARY OF THE INVENTION

It has been found that aqueous solutions of nonsteroidaltriphenylethylene antiestrogens and their pharmaceutically acceptablesalts with high drug concentrations can be prepared by using as asolubility enhancing agent a pharmaceutically acceptable mono- ordicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain mayfurther contain 1-4 hydroxyl, 1-3 oxo, or one or several halogensubstituents, or a corresponding anion thereof, or methanesulfonic acidor its corresponding anion, in molar excess with respect to thetriphenylethylene antiestrogen. Furthermore, it was found that pH ofsuch formulations can be increased to nearly neutral withoutprecipitation of the triphenylethylene drug if the solubility enhancingagent is used together with an organic water miscible co-solvent,preferably polyethylene glycol (PEG), propylene glycol, ethanol orisopropanol or a combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an aqueous composition of a nonsteroidaltriphenylethylene antiestrogen or a pharmaceutically acceptable saltthereof comprising as a solubility enhancing agent a pharmaceuticallyacceptable mono- or dicarboxylic acid having 1-5 carbon atoms, whereinthe carbon chain may further contain 114 hydroxyl, 1-3 oxo, or one orseveral halogen substituents, or a corresponding anion thereof, ormethanesulfonic acid or its corresponding anion, in molar excess withrespect to the triphenylethylene antiestrogen.

The present invention also provides an aqueous composition of anonsteroidal triphenylethylene antiestrogen or a pharmaceuticallyacceptable salt thereof comprising as a solubility enhancing agent apharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbonatoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3oxo, or one or several halogen substituents, or a corresponding anionthereof, or methanesulfonic acid or its corresponding anion, in molarexcess with respect to the triphenylethylene antiestrogen together withan organic water miscible co-solvent.

The present invention further provides a method for preparing aqueouscomposition of a nonsteroidal triphenylethylene antiestrogen or apharmaceutically acceptable salt thereof comprising contacting anonsteroidal triphenylethylene antiestrogen or a pharmaceuticallyacceptable salt thereof with aqueous media and a solubility enhancingagent selected from a group consisting of a pharmaceutically acceptablemono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbonchain may further contain 1-4 hydroxyl, 1-3 oxo, or one or severalhalogen substituents, or a corresponding anion thereof, ormethanesulfonic acid or its corresponding anion, in molar excess withrespect to the triphenylethylene antiestrogen.

The present invention also provides a method for preparing aqueouscomposition of a nonsteroidal triphenylethylene antiestrogen or apharmaceutically acceptable salt thereof comprising contacting anonsteroidal triphenylethylene antiestrogen or a pharmaceuticallyacceptable salt thereof with aqueous media, an organic water miscibleco-solvent and a solubility enhancing agent selected from a groupconsisting of a pharmaceutically acceptable mono- or dicarboxylic acidhaving 1-5 carbon atoms, wherein the carbon chain may further contain1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or acorresponding anion thereof, or methanesulfonic acid or itscorresponding anion, in molar excess with respect to thetriphenylethylene antiestrogen.

The solubility enhancing agent is used in molar excess with respect tothe nonsteroidal triphenylethylene antiestrogen. Preferably, thesolubility enhancing agent is used in at least about 1.5 fold, morepreferably at least about 2 fold, molar excess, e.g. from about 2 toabout 100 fold, typically from about 2 to about 10 fold, with respect tothe nonsteroidal triphenylethylene antiestrogen.

The carbon chain of the solubility enhancing agent of the invention maybe straight or branched, saturated or unsaturated carbon chain.

Suitable solubility enhancing agents having branched carbon chaininclude citramalic acid and isobutyric acid, and the correspondinganions.

Suitable solubility enhancing agents having straight carbon chaininclude lactic acid, acetic acid, formic acid, methanesulfonic acid,3-hydroxybutyric acid, glycolic acid, pyruvic acid, acrylic acid,propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleicacid, tartaric acid and glutaric acid or the corresponding anions(lactate, acetate, formate, mesylate, 3-hydroxybutyrate, glycolate,pyruvate, acrylate, propionate, trifluoroacetate, oxalate, malonate,maleate, tartrate and glutarate).

Preferred solubility enhancing agents are mono or dicarboxylic acidshaving 1-4 carbon atoms and dicarboxylic acids having 5 carbon atoms,wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, orone or several, e.g. 1-3, halogen substituents and the correspondinganions. Preferred halogen substituent is fluorine.

More preferred are mono- or dicarboxylic acids having 1-3 carbon atomsand dicarboxylic acids having 5 carbon atoms, wherein the carbon chainmay further contain 1-2 hydroxyl or 1 oxo substituent, and thecorresponding anions. Such solubility enhancing agents include lacticacid, acetic acid, formic acid, glycolic acid, pyruvic acid, acrylicacid, propionic acid, glutaric acid, oxalic acid or malonic acid, or thecorresponding anions.

Still more preferred are monocarboxylic acids having 1-3 carbon atomsand dicarboxylic acids having 5 carbon atoms, wherein the carbon chainmay further contain 1-2 hydroxyl substituent, and the correspondinganions. Lactic acid, acetic acid, formic acid, glycolic acid andglutaric acid and the corresponding anions are particularly preferred.Lactic acid and the corresponding anion (lactate) are most preferred.

Preferably the organic water miscible co-solvent is polyethylene glycol(PEG), propylene glycol, ethanol or isopropanol or a combinationthereof. The amount of the organic water miscible co-solvent is usuallyfrom about 1% to about 75%, preferably from about 5% to about 50%, morepreferably from about 10% to about 30%, by weight of the formulation.

The formulations of the invention can be prepared e.g. by mixing theacid and/or corresponding salt thereof, purified water, and optionallythe organic water miscible co-solvent together, and adding thereaftertriphenylethylene antiestrogen or salt thereof and agitating themixture. For example, up to about 50 w-% solutions of atriphenylethylene antiestrogen or salt thereof can be prepared usingthis procedure. pH of the solution may be adjusted with a water solutionof the corresponding acid salt or e.g. sodium hydroxide. Generally, whenpH is increased, solubility of a triphenylethylene antiestrogen isdecreased. However, by using the organic water miscible co-solvent ofthe invention solutions having pH only slightly acidic or nearly neutralcan be prepared. Highest drug concentrations are obtained when the pH ofthe solution is below 7, in particular below pH 6. Preferably the pH ofthe formulation of the invention is between 4 and 7, more preferablybetween 5 and 7.

Various additives used in the art such as preservatives, e.g. parabens,sodium benzoate or benzoic acid, or various combinations thereof may beused. The solutions of the invention are suitable in the preparation ofe.g. high concentration parenteral, transdermal or topical formulations.

The following experiments demonstrate that the water-solubility of anonsteroidal triphenylethylene antiestrogen or a pharmaceuticallyacceptable salt thereof can be dramatically improved by using thesolubility enhancing agent according to the invention. The experimentsalso compare the effect of solubility enhancing agents of the inventionto other acids such as hydrochloric acid, gluconic acid or citric acid.The experiments also demonstrate that by using an organic water miscibleco-solvent according to the invention pH of the solutions can beincreased without precipitation of the drug, even if the organic watermiscible co-solvents of the invention alone are not able tosignificantly solubilize the drug.

Experiments

EXAMPLE 1 Aqueous Formulation of Toremifene Using Acetic Acid as aSolubility Enhancing Agent (% is Calculated by Weight of theComposition)

Toremifene base 18.4% Glacial acetic acid 9.0% Purified water 72.6%Glacial acetic acid and purified water were mixed, toremifene base wasadded and dissolved. pH of the solution was about 4.

EXAMPLE 2 Aqueous Formulation of Toremifene Using Lactic Acid as aSolubility Enhancing Agent

Toremifene base 52.6% Lactic acid (85%) 24.0% Purified water 23.4%Lactic acid (85% water solution) and purified water were mixed,toremifene base was added and dissolved.

EXAMPLE 3 Aqueous Formulation of Toremifene Using Formic Acid as aSolubility Enhancing Agent

Toremifene base 8.2% Formic acid 1.6% Purified water 90.2%Formic acid and purified water were mixed, toremifene base was added;toremifene dissolved slowly (in 3 hours).

EXAMPLE 4 Aqueous Formulation of Toremifene Using Methanesulfonic Acidas a Solubility Enhancing Agent

Toremifene base 16.7% Methanesulfonic acid 66.6% Purified water 16.7%Toremifene base was dissolved in methanesulfonic acid, then purifiedwater was added. A clear solution was obtained.

EXAMPLE 5 Aqueous Formulation of Tamoxifen Base Using Acetic Acid as aSolubility Enhancing Agent

Tamoxifen base 44.2% Glacial acetic acid 27.9% Purified water 27.9%Glacial acetic acid and purified water were mixed, tamoxifen base wasadded and dissolved.

EXAMPLE 6 Aqueous Formulation of Tamoxifen Base Using Lactic Acid as aSolubility Enhancing Agent

Tamoxifen base 44.0% Lactic acid (85%) 28.0% Purified water 28.0%Lactic acid (85% water solution) and purified water were mixed,tamoxifen base was added and dissolved.

EXAMPLE 7 Aqueous Formulation of Tamoxifen Base Using Formic Acid as aSolubility Enhancing Agent

Tamoxifen base 5.0% Formic acid 10.4% Purified water 84.6%Formic acid and purified water were mixed, tamoxifen base was added anddissolved.

EXAMPLE 8 Aqueous Formulation of Tamoxifen Base Using MethanesulfonicAcid as a Solubility Enhancing Agent

Tamoxifen base 16.7% Methanesulfonic acid 66.6% Purified water 16.7%Tamoxifen base and methanesulfonic acid were mixed, then purified waterwas added. A clear solution was obtained.

EXAMPLE 9 Aqueous Formulation of Toremifene Using Lactic Acid/Lactate asa Solubility Enhancing Agent, pH 5

Toremifene base 3.7% Lactic acid (85%) 1.7% Sodium lactate (50%) 4.4%Purified water 90.2%Lactic acid and purified water were mixed, toremifene base was added anddissolved. pH was adjusted to about 5 by sodium lactate (50% watersolution).

EXAMPLE 10 Aqueous Formulation of Toremifene Using Lactic Acid as aSolubility Enhancing Agent, pH 5

Toremifene base 36.3% Lactic acid (85%) 18.2% Sodium hydroxide 2 M 27.3%Purified water 18.2%Lactic acid and purified water were mixed, toremifene base was added anddissolved. pH was adjusted to about 5 with 2 M sodium hydroxide.

EXAMPLE 11 Reference

Toremifene base 9.1% Hydrochlorid acid 1 N 31.8% Purified water 59.1%Hydrochloric acid and purified water were mixed, toremifene base wasadded. Toremifene was not dissolved.

EXAMPLE 12 Reference

Toremifene base 1.0% Gluconic acid (30%) 10.6% Ethanol (96%) 88.3%Toremifene base and 30% water solution of gluconic acid were mixedtogether and ethanol was gradually added. Toremifene was not dissolved.

EXAMPLE 13 Aqueous Formulation of Toremifene Using Lactic Acid/Lactateand Ethanol, pH About 6

Toremifene base 13.6% Lactic acid (85%) 6.8% Purified water 13.6% Sodiumlactate (50%) 52.4% Ethanol (96%) 13.6%Toremifene base was dissolved to the solution of lactic acid andpurified water. Ethanol was added and pH was increased by adding sodiumlactate. The formulation above was a clear solution, pH about 6.

EXAMPLE 14 Aqueous Formulation of Toremifene Using Lactic Acid/SodiumHydroxide and Ethanol, pH About 6

Toremifene base 36.60% Lactic acid (85%) 18.35% Purified water 18.35%Sodium hydroxide (10 M)  8.35% Ethanol (96%) 18.35%Toremifene base was dissolved to the solution of lactic acid andpurified water. Ethanol was added and pH was increased by adding sodiumhydroxide. The formulation above was a clear solution, pH about 6.

EXAMPLE 15 Aqueous Formulation of Toremifene Using Lactic Acid/SodiumHydroxide and PEG 400A

Toremifene base 27.5% Lactic acid (85%) 13.75% Purified water 27.5%Sodium hydroxide (10 M)  3.75% PEG 400A 27.5%Toremifene base was dissolved to the solution of lactic acid andpurified water. PEG 400A was added and pH was increased by adding sodiumhydroxide. The formulation above was a clear solution, pH about 6.

EXAMPLE 16 Aqueous Formulation of Toremifene Using Lactic Acid/Lactateand Isopropanol

Toremifene base 17.7% Lactic acid (85%)  9.3% Purified water 18.5%Sodium lactate (50%) 36.0% Isopropanol 18.5%Toremifene base was dissolved to the solution of lactic acid andpurified water. Isopropanol was added and pH was increased by addingsodium lactate. The formulation above was a clear solution, pH about 5.

EXAMPLE 17 Aqueous Formulation of Tamoxifen Using Lactic Acid/Lactateand Ethanol

Tamoxifen base 11.1% Lactic acid (85%)  5.5% Purified water 11.1% Sodiumlactate (50%) 61.1% Ethanol (96%) 11.2%Tamoxifen base was dissolved to the solution of lactic acid and purifiedwater. Ethanol was added and pH was increased by adding sodium lactate.The formulation above was a clear solution, pH about 6.

EXAMPLE 18 Aqueous Formulation of Tamoxifen Using Lactic Acid/SodiumHydroxide and Ethanol

Tamoxifen base 36.5% Lactic acid (85%) 18.3% Purified water 18.3% Sodiumhydroxide (10 M)  8.6% Ethanol (96%) 18.3%Tamoxifen base was dissolved to the solution of lactic acid and purifiedwater. Ethanol was added and pH was increased by adding sodiumhydroxide. The formulation above was a clear solution, pH about 6.

EXAMPLE 19 Aqueous Formulation of Tamoxifen Using Lactic Acid/Lactateand PEG 400A

Tamoxifen base 22.2% Lactic acid (85%) 11.1% Purified water 22.3% Sodiumlactate (50%) 22.2% PEG 400A 22.2%Tamoxifen base was dissolved to the solution of lactic acid and purifiedwater. PEG 400A was added and pH was increased by adding sodium lactate.The formulation above was a clear solution, pH about 5.

EXAMPLE 20 Aqueous Formulation of Tamoxifen Using Lactic Acid/Lactateand Isopropanol

Tamoxifen base 22.2% Lactic acid (85%) 11.1% Purified water 22.3% Sodiumlactate (50%) 22.2% Isopropanol 22.2%Tamoxifen base was dissolved to the solution of lactic acid and purifiedwater. Isopropanol was added and pH was increased by adding sodiumlactate. The formulation above was a clear solution, pH about 5.

EXAMPLE 21 Aqueous Formulation of Toremifene Citrate Using Lactate, PEG300 and Ethanol

Toremifene citrate 15% Purified water 20% Sodium lactate (50%) 40% PEG300 15% Ethanol (96%) 10%Toremifene citrate was added to the mixture of all the other components.The formulation above was a clear solution, pH about 5.

EXAMPLE 22 Aqueous Formulation of Toremifene Using-Lactic Acid/SodiumHydroxide, PEG 300 and Ethanol, pH About 6.

Toremifene base 28.10% Purified water 14.05% Lactic acid (85%) 11.1% PEG300 29.20% Ethanol (96%) 14.05% Sodium hydroxide (10 M)  0.55%Toremifene base was dissolved to the solution of lactic acid andpurified water. PEG 400A and ethanol was added and pH was increased byadding sodium hydroxide. The formulation above was a clear solution, pHabout 6.

EXAMPLE 23 Aqueous Formulation of Toremifene Using Acetic Acid andEthanol

Toremifene base 17.5% Acetic acid  8.7% Ethanol (96%) 73.8%Glacial acetic acid and ethanol were mixed, toremifene base was addedand dissolved.

EXAMPLE 24 Aqueous Formulation of Toremifene Using Acetic Acid/SodiumHydroxide and Ethanol

Toremifene base 14.6% Acetic acid  7.3% Ethanol (96%) 29.4% Purifiedwater 43.9% Sodium hydroxide (10 M)  4.8%Toremifene base was dissolved to the solution of acetic acid andpurified water. Ethanol was added and pH was increased by adding sodiumhydroxide. The formulation above was a clear solution, pH about 6.

EXAMPLE 25 Aqueous Formulation of Toremifene Using Lactic Acid/Lactate,Propylene Glycol and Ethanol

Toremifene base 13.3% Purified water 13.3% Lactic acid (85%)  6.7%Sodium lactate (50%) 53.3% Propylene glycol  6.7% Ethanol (96%)  6.7%Toremifene base was dissolved to the solution of lactic acid andpurified water. Ethanol and propylene glycol were added and pH wasincreased by adding sodium lactate. The formulation above was a clearsolution, pH about 6.

EXAMPLE 26 Aqueous Formulation of Toremifene Using 20% Water Solution ofGlycolic Acid/Sodium Hydroxide and Ethanol

Toremifene base  8.3% Glycolic acid (20%) 41.5% Ethanol (96%) 42.1%Sodium hydroxide (10 M)  8.1%Toremifene base was dissolved to the 20% water solution of glycolicacid. Ethanol was added and pH was increased by adding sodium hydroxide.The formulation above was a clear solution, pH about 5.

EXAMPLE 27 Aqueous Formulation of Toremifene Using 30% Water Solution ofPyruvic Acid/Sodium Hydroxide and Ethanol

Toremifene base  7.6% Pyruvic acid (30%) 41.1% Ethanol (96%) 38.6%Sodium hydroxide (10 M) 12.7%Toremifene base was dissolved to the 30% water solution of pyruvic acid.Ethanol was added and pH was increased by adding sodium hydroxide. Theformulation above was a clear solution, pH about 5.

EXAMPLE 28 Aqueous Formulation of Toremifene Using 20% Water Solution ofAcrylic Acid/Sodium Hydroxide and Ethanol

Toremifene base  8.2% Acrylic acid (20%) 40.4% Ethanol (96%) 42.8%Sodium hydroxide (10 M)  8.6%Toremifene base was dissolved to the 20% water solution of acrylic acid.Ethanol was added and pH was increased by adding sodium hydroxide. Theformulation above was a clear solution, pH about 5.

EXAMPLE 29 Aqueous Formulation of Toremifene Using 23% Water Solution ofPropionic Acid/Sodium Hydroxide and Ethanol

Toremifene base  8.1% Propionic acid (20%) 41.9% Ethanol (96%) 41.0%Sodium hydroxide (10 M)  8.9%It was made a 20% mixture of propionic acid anhydride in water. Themixture was allowed to stand for four days at room temperature. Afterfour days it was assumed that all propionic acid anhydride had reactedwith water to make about 23% water solution of propionic acid.Toremifene base was dissolved to this 23% water solution of propionicacid. Ethanol was added and pH was increased by adding sodium hydroxide.The formulation above was a clear solution, pH about 5.

EXAMPLE 30 Aqueous Formulation of Toremifene Using TrifluoroaceticAcid/Sodium Hydroxide and Ethanol

Toremifene base  5.2% Trifluoroacetic acid 26.3% Purified water 17.7%Ethanol (96%) 26.2% Sodium hydroxide (10 M) 24.6%Toremifene base was dissolved to trifluoroacetic acid. When water wasadded, the mixture became cloudy. When ethanol was added, the mixturebecame clear again. pH was increased by adding sodium hydroxide. Theformulation above was a clear solution, pH about 2. It should bepossible to raise pH to a more neutral value, because trifluoroacetic isalready almost totally neutralised at pH 2.

EXAMPLE 31 Aqueous Formulation of Toremifene Using 10% Water Solution ofOxalic Acid Dihydrate and Ethanol

Toremifene base 2.4% Oxalic acid dihydrate (10%) 61.0% Ethanol (96%)36.6%Toremifene base was mixed with 10% water solution of oxalic aciddihydrate. When ethanol was added, a clear solution was obtained.

EXAMPLE 32 Aqueous Formulation of Toremifene Using 40% Water Solution ofMalonic Acid/Sodium Hydroxide and Ethanol

Toremifene base 4.4% Malonic acid (40%) 44.5% Ethanol (96%) 22.9% Sodiumhydroxide (10 M) 28.2%Toremifene base was dissolved to the 40% water solution of malonic acid.Ethanol was added and pH was increased by adding sodium hydroxide. Theformulation above was a clear solution, pH about 6.

EXAMPLE 33 Aqueous Formulation of Toremifene Using 30% Water Solution ofMaleic Acid and Ethanol

Toremifene base 8.8% Maleic acid (30%) 44.7% Ethanol (96%) 46.5%Toremifene base was mixed with 30% water solution of maleic acid. Whenethanol was added, a clear solution was obtained.

EXAMPLE 34 Aqueous Formulation of Toremifene Using 30% Water Solution ofTartaric Acid and Ethanol

Toremifene base 9.1% Tartaric acid (30%) 45.4% Ethanol (96%) 45.5%Toremifene base was mixed with 30% water solution of tartaric acid. Whenethanol was added, a clear solution was obtained.

EXAMPLE 35 Aqueous Formulation of Toremifene Using 30% Water Solution ofGlutaric Acid/Sodium Hydroxide and Ethanol

Toremifene base 7.2% Glutaric acid (30%) 40.1% Ethanol (96%) 37.0%Sodium hydroxide (10 M) 15.7%Toremifene base was dissolved to the 30% water solution of glutaricacid. Ethanol was added and pH was increased by adding sodium hydroxide.The formulation above was a clear solution, pH about 6.

EXAMPLE 36 Aqueous Formulation of Toremifene Using 25% Water Solution of3-Hydroxybutyric Acid/Sodium Hydroxide and Ethanol

Toremifene base 2.9% 3-hydroxybutyric acid (25%) 57.3% Ethanol (96%)28.9% Sodium hydroxide (10 M) 10.9%It was made a 30% solution of 3-hydroxybutyric acid sodium salt inwater. The solution was made acidic with hydrochloric acid (pH about 1).Toremifene base and this 25% water solution of 3-hydroxybutyric acidwere mixed together. When ethanol was added, toremifene dissolved. pHwas increased by adding sodium hydroxide. The formulation above was aclear solution, pH about 6.

EXAMPLE 37 Reference

Toremifene base 1.0% Citric acid (30%) 10.3% Ethanol (96%) 88.7%Toremifene base and 30% water solution of citric acid were mixedtogether and ethanol was added gradually. Toremifene was not dissolved.

EXAMPLE 38 Reference

Toremifene citrate 1.0% PEG 300 99.0%Toremifene citrate was not dissolved to the PEG 300 solution.

EXAMPLE 39 Reference

Solubility of toremifene citrate in ethanol is about 3 mg/ml.

EXAMPLE 40 Reference

Solubility of toremifene citrate in 0.1 M HCl is about 0.03 mg/ml.

1. An aqueous solution of a nonsteroidal triphenylethylene antiestrogenor a pharmaceutically acceptable salt thereof, comprising thenonsteroidal triphenylethylene antiestrogen or pharmaceuticallyacceptable salt thereof and, as a solubility enhancing agent, apharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbonatoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3oxo, or one or several halogen substituents, or a corresponding anionthereof, or methanesulfonic acid or its corresponding anion, in molarexcess with respect to the triphenylethylene antiestrogen, with theproviso that the monosteroidal triphenylethylene antiestrogen orpharmaceutically acceptable salt thereof is not in the form ofcyclodextrin inclusion complex.
 2. An aqueous solution of claim 1,comprising together with the solubility enhancing agent an organic watermiscible co-solvent.
 3. An aqueous solution of claim 2, wherein theco-solvent is polyethylene glycol (PEG), propylene glycol, ethanol orisopropanol.
 4. An aqueous solution according to claim 1, wherein thesolubility enhancing agent is used in at least about 1.5 fold molarexcess with respect to the nonsteroidal triphenylethylene antiestrogen.5. An aqueous solution according to claim 1, having a pH value from 4 to7.
 6. An aqueous solution according to claim 1, wherein the nonsteroidaltriphenylethylene antiestrogen is toremifene, tamoxifen, droloxifene,4-hydroxytamoxifen, idoxifene, raloxifene, levormeloxifene, centchroman,clomiphene or a pharmaceutically acceptable salt thereof.
 7. A methodfor preparing an aqueous solution of a nonsteroidal triphenylethyleneantiestrogen or a pharmaceutically acceptable salt thereof, comprisingcontacting the nonsteroidal triphenylethylene antiestrogen orpharmaceutically acceptable salt thereof with aqueous media and asolubility enhancing agent selected from the group consisting of apharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbonatoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3oxo, or one or several halogen substituents, or a corresponding anionthereof, or methanesulfonic acid or its corresponding anion, in molarexcess with respect to the triphenylethylene antiestrogen, with theproviso that the nonsteroidal triphenylethylene antiestrogen or apharmaceutically acceptable salt thereof is not in the form ofcyclodextrin inclusion complex.
 8. A method for preparing an aqueoussolution of a nonsteroidal triphenylethylene antiestrogen or apharmaceutically acceptable salt thereof comprising contacting thenonsteroidal triphenylethylene antiestrogen or pharmaceuticallyacceptable salt thereof with aqueous media, an organic water miscibleco-solvent and a solubility enhancing agent selected from the groupconsisting of a pharmaceutically acceptable mono- or dicarboxylic acidhaving 1-5 carbon atoms, wherein the carbon chain may further contain1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or acorresponding anion thereof, or methanesulfonic acid or itscorresponding anion, in molar excess with respect to thetriphenylethylene antiestrogen, with the proviso that the nonsteroidaltriphenylethylene antiestrogen or a pharmaceutically acceptable saltthereof is not in the form of cyclodextrin inclusion complex.
 9. Amethod of claim 8, wherein the co-solvent is polyethylene glycol (PEG),propylene glycol, ethanol or isopropanol.
 10. An aqueous solutionaccording to claim 1, wherein the solubility enhancing agent is used inat least about 2 fold, molar excess with respect to the nonsteroidaltriphenylethylene antiestrogen.